Concentrated liquid lactic acid douche preparation containing aromatics



United States Patent 3,346,451 CON CENTRATED LIQUID LACTIC ACID DOUCHEPREiARATION CONTAINING AROMATICS Galen F. Collins and Oscar L. Butt,Bristol, Tenn., as-

signors to The S. E. Massengill Company, Bristol,

Tenn., a corporation of Tennessee No Drawing. Filed Jan. 27, 1965, Ser.No. 428,566

5 Claims. (Cl. 167-58) This invention in one of its aspects pertains toliquid douche compositions. In one of its more particular aspects theinvention relates to liquid douche compositions which, although inaqueous phase, nevertheless contain aromatics. The term aromatics asused in connection with douches in powder form is well known and isunderstood to encompass one or more of menthol, thymol, oil ofeucalyptus, methyl salicylate, and the like, all of which are virtuallyinsoluble in water. See Modern Drug Encyclopedia and Therapeutic Index,Drug Publications, Inc.

A study of textbooks on gynecology reveals divergent views on douching.Some physicians advocate acid douches; some prefer alkaline douches; andthere are those who advocate no douching. It is generally believed,however, that while many vaginal symptoms can be cleared up only by theremoval of deep-seated causes, the therapeutic vaginal douche serves asan important adjuvant in the treatment of such conditions. In addition asurprising number of minor infections appear to be cured by the use ofacid douche preparations.

It has been reported that alkaline douches have no application intherapy of vaginitis. Vaginal therapy for irichomonas vaginalisvaginitis depends upon the restoration of the vaginal pH to a normalrange of 3.5 to 5. Treatment for vaginalis vaginitis and for nonspecificvaginitis consists of acid douching. The selection of a suitable doucheis, therefore, a matter of great importance to the clinician.

This invention is concerned with acid douche preparations used torestore and maintain an acid pH corresponding to that of the normallactobacillary flora of the vaginal tract. These are liquid preparationsused as adjuncts in the management of vaginal and cervical infectionsdue to trichomonas and other vagino-cervicitis in- 3,346,451 PatentedOct. 10, 1967 since the product does not require any significantstirring for preparation for use. A liquid also lends itself tomeasuring devices such as bottle caps which find better consumeracceptance.

In spite of the advantages of liquid douche preparations they have notbeen as widely accepted as powder douche products. One reason for thisis believed to be that liquid douche preparations do not include theeffective aromatics. Experience has shown that combinations haveexcellent acceptance by users of powder douche products which containmenthol, oil of eucalyptus, methyl salicylate and thymol, and variousmixtures of these. These aromatics have such low solubility in waterthey have heretofore been used only in powders. Powder douchepreparations are highly diluted with water; this permits solution of thearomatics.

One possible method for incorporating aromatics in a liquid douchepreparation would be to dissolve the aromatics in a water-solublealcohol and dissolve this alcohol solution of aromatics in water.However in the case of an acid douche, an alcohol-acid reaction ispossible. Desirable acid douches should provide a pH between 3.5 and 5with good buifer capacity. The acidalcohol reaction and accompanyingester formation will raise the pH and reduce the butter capacity of thedouche reparation. It is therefore not possible to maintain the desiredpH if a reaction occurs between the acidic material and the alcohol. Inaddition esters introduce unexpected odors or a foreign substanceundesirable from a psychological standpoint.

In accordance with one aspect of this invention is has been found thatthe combination of lactic acid and ethyl alcohol can be used in a liquiddouche preparation with essentially no reaction of alcohol with acid. Anindication of the alcohol-acid reaction is the percent titratibleacidity. This percent acidity is determined from cubic centimeters ofstandard sodium hydroxide, titrating with 0.1 N sodium hydroxide using aphenolphthalein end point. The percent acidity decreases with increasingalcoholacid reaction. Acetic acid has a dissociation constant of 1.75 Xl0 whereas lactic acid has a dissociation constant of 8.4' l0-*. Itwould be expected therefore that lactic acid would form esters at aboutthe same rate as acetic acid. 'The following data show that this is notthe case.

TABLE I.-ESTERIFICATION TEST Composition A Composition B Acetic Acid,

gm Ethyl Alcohol 95%, ml Sodium Hydroxide, gm Water, q.s., ml pH,approximately Lactic Acid, gm Ethyl Alcohol m1. Sodium Hydroxide, gmWater, q.s., m1 pH, approximately ACID ITY Percent Acidity IngredientTime Elapsed CRT 40 C. 50 0.

Composition:

Acetic Acid in 30% Ethanol 1 month.-. 9 months" Initial 1 month--- 9months Lactic Acid in 30% Ehtanol fections. There are certain advantagesto the use of liquid douche preparations for feminine hygiene. A liquidpreparation has all of the active ingredients dissolved. This eliminatespossible irritations that may occur in the case of powder douchepreparations due to the fact that all of the solid materials or oils arenot in solution prior to use. Moreover a liquid preparation is easier touse The foregoing data show that in the case of acetic acid, commonlyemployed in douche preparations, there is a drop in the percent acidityat controlled room temperature (CRT) from 12.33 to 10.18 in 9 months. Inthe lactic acid preparation the acidity change for the same period andtemperature is 11.12 to 11.34. (The slight increase is believed due tothe presence of anhydride.) At 40 C with the acetic acid preparation,the acidity is 10.92, at the end of the first month and 9.32 at the endof 9 months. With the composition of this invention the percent aciditychanged from 11.73 at the end of one month to 10.89 at-the end of 9months. It can be seen, therefore, that very little reaction occursbetween ethyl alcohol and lactic acid. Such is not the case with ethylalcohol and acetic acid.

In accordance with another aspect of this invention the combination oflactic acid and isopropanol, although less desirably, will also functionas a vehicle for the introduction of aromatics into the douchecomposition. The

dropped from 12.33 to 11.91 in one month at room temperature, whereasthe lactic acid composition C, at room temperature exhibited noappreciable change.

Now consider citric acid which is also frequently used in douchepreparations. This acid has dissociation constants of 8.4X10- 1.8 10 and4.0X- Citric acid likewise would be expected to be similar to lacticacid in its reaction with ethyl alcohol. Rather, a reaction occurs as inthe case of acetic acid, rendering it unsuitable for a liquid douchepreparation containing aromatics. The esterification of citric acid byreaction with the ethanol is shown in the following table.

TABLE III.ESTERIFICATION TEST Composition D:

data in the following table show that ester formation also is not asignificant factor in this combination. The use of this combination ishampered only by the odor of the alcohol which requires difierentproportions of the various aromatics.

TABLE IL-ESTERIFICATION TEST Composition 0:

Lactic acid 85%, e

The data in Table 111 show a significant reduction in percent titratibleacidity, indicating considerable reaction between the citric acid andthe ethanol. Citric acid, like acetic acid, is unsuitable for liquiddouche preparations containing ethyl alcohol.

Isopropyl alcohol 30%, gm. Sodium hydroxide, Q'm Water, q.s., m

5 w re 9 2" con-ea pH, approximately 3. 5.

ACIDITY Percent Acidity Ingredient Time Elapsed CRT 40 C. C.

Composition: Tn flail 9, 03

1 month--. 10.1 10. 7 10. 5 C Lactic Acid in 30% IsopropanoL- 2 months-.10. 5 10.9 10. 5 3 months 10.7 10.4 9. 9 5 months.. 10.7 1 9.8 Tnii'ial12, 33 A Acetic Acid in 30% Ethanol-- {1 month--- 11. 91 10. 92 9.95 9months.- 10.18 9. 32 8. 99

Here again very little change in percent acdity, which would indicateester formation, is noted compared to the acetic acid-ethanolcombination. Thus, acetic acid-ethanol It has been pointed out that inaddition to providing a pH of 3.5 to 5 an eifective liquid douche shouldhave good buiier capacity. Buffer capacities can best be dis- TABLEIV.BUFFER INDEX Butler Index Time Elapsed Ingredient Composition:

Acetic Acid in 30% Ethanol 9 months.. Initial--- 1 month... 2 months- 3months.. 5 months.. Initial.. 1 month..- 2 months. 3 months-. 5 months-Lactic Acid in 30% Ethanol-. {I mont Lactic Acid in 30% IsopropanolCitric Acid in 30% Ethanol.

cussed in terms of the buifer index. Buffer index is the increment ofbase required to produce an increment in the pH value of the solution.Butter index as used herein is the amount of standard sodium hydroxide,expressed in millimoles, necessary to produce an increase from theoriginal pH to pH 6.0.

Calculation: BuiI'er index: Millimoles of NaOH=ml. of NaOI-I addedxnormality of NaOH.

It can be seen from Table IV that the two acids A and D, widely used inliquid douches devoid of alcohol, do not have the buffer capacity whichcompositions B and C of this invention possess. There is a marked dropin butter index in the tests conducted with compositions A and D whereasthere is little or no drop in buffer index in the case of compositions Band C.

Lactic acid thus lends itself admirably to concentrated liquid douchepreparations wherein C alcohols, and to a lesser extent, C alcohols areemployed as the vehicle for the introduction of the aromatics. Accordingto an aspect of this invention therefore, a liquid douche preparationcontaining aromatics is provided, which is water dilutable, to form anaqueous douche for restoring and maintaining a normal vaginal pH. Thedouche preparation is a buffered aqueous solution of lactic acid havinga pH of 3.5 to 5. It contains (1) a surfactant or wetting agent, and,(2) dissolved therein, a C or C alcohol solution of aromatics, thelactic acid permitting solution with essentially no reaction of alcoholwith lactic acid to raise the pH. i

The douche preparation of this invention desirably is diluted 100 to1000 parts to 1 by volume and will usually be sold with a devicedispensing an amount to which a quart of water should be added. A douchepreparation must, of course, not be harsh or irritating if used instronger dilution since experience has shown that exact dilutions willnot be used due to carelessness. The preparation of this invention canbe so used.

This first aspect of the invention thus provides a liquid lactic aciddouche preparation containing aromatics for use in the restoration ofthe vaginal pH to a normal range of 3.5 to 5, this aqueous douchecomposition containing 96 to 74 Weight percent lactic acid as an activeingredient; 2 to 14 weight percent of a surfactant; and 2 to 12 weightpercent aromatics, the total being 100 percent. The buffer ing is wellknown, sufiicient alkali being used to adjust the pH in the 3.5 to 5range. Other ingredients such as known astringents, colorants and thelike can, of course, be added. The percentages of theforcgoing essentialingredients will not change regardless of the quantity of alcohol, wateror other ingredients added. The alcohol employed in the concentratedcomposition generally will be sufficient to dissolve the aromatics up tofifty percent of the water in the concentrate.

In the preparation of the douche compositions of this invention thearomatics can be dissolved in the ethanol and the water-solubleingredients dissolved in water. The two solutions are then combined.Another method is illustrated in the following example. In use, ml. ofthe preparation is added to a quart (approximately 1000 ml.) of water.Accordingly, the examples herein are based on 10 ml. doses.

EXAMPLE A (Per 10 ml. dose) Lactic acid (USP. 85%) gm 1.5 Sodiumhydroxide gm 0.30 Tartrazine F. D. and C. Yellow No. 5 mg 0.25 Quinolineyellow, water soluble D. and C. Yellow No. 10 mg 1.50 Alcohol (U.S.P.95%) cc 3.15

6 EXAMPLE AContinued Octylphenoxy polyethoxy ethanol Triton The lacticacid and sodium hydroxide are dissolved in half of the water (5 1111.).In the other half of the water the quinoline and tartrazine colorantsare dissolved. The two 5 ml. moieties are then combined and the alcohol,Triton X- and aromatics are added to the solution. The composition canbe filtered if necessary. When 10 ml. of the liq id is added to 1 quartof water, a pH of about 3.6 results with a surface tension of about 30dynes. The solution has a buffer index of about 10. Sodium hydroxide isnot a buffering agent as such, but when it reacts with lactic acid, itforms sodium lactate, and sodium lactatelactic acid is the bufferingagent. Potassium hydroxide can be used as a replacement for the sodiumhydroxide.

In the formulation of Example A the No. 10 and No. 5 colorants, thesurfactant and the solution of aromatics are conventional. It is obviousthat changes in these ingredients can be made without affecting thetherapeutic objective. Thus other colorants such as Rhodamine BHydrochloride (D. and C. Red No. 19) and Brilliant Blue PCP (F. D. andC. Blue No. l) as well as other nonionic and anionic surfactants such assodium lauryl sulfate, lauryl amide polyether, nonylphenoxy polyetherethanols and octylphenoxy polyether ethanols With three to thirtyoxyethylene groups, and the like can be used. The sodium hydroxide, onthe other hand, is used to provide the desired hydrogen ionconcentration. Potassium hydroxide and other inorganic bases can besubstituted therefor.

Douche preparations formulated according to the aspect of this inventionwhich has been described are excellent for use by physicians who prefera lactic acid douche physician and the patient. It maintains the normalvaginal pH. It has cleansing and antiseptic properties due to thesurfactant. It is safe, and it contains the aromatics which experiencehas shown are in greater demand.

Many physicians, however, prefer that a douche preparation also havemild astringent properties. One of the features of this invention isthat mildly astringent compounds such as aluminum lactate and aluminumphenol sulfonate can be included in the formulation, frequently in lieuof sodium hydroxide. Potassium and ammonium alum, which are often usedin douche products for their astringency, cannot be employed in theliquid lactic acid douche preparations of this invention because oftheir poor solubility in the alcohol which is required for solution ofthe aromatic constituents. Likewise boric acid and citric acid cannot beused in liquid preparations with aluminum salts, since both aluminumborate and aluminum citrate are relatively insoluble. In another of itsaspects this invention provides a unique combination of astringentswhich overcome this solubility problem. Moreover, in accordance With thepractice of this aspect of the invention novel astringents have beenfound which in combination with lactic acid produce the normal vaginalpH. This aspect of the invention contemplates the use of an aluminumchlorhydroxide complex [Al (OH) C-1] wherein x is one to ten, andaluminum chloride in combination with lactic acid to provide a douchepreparation with astringent properties. The following exampleillustrates the preparation of a liquid douche product of this aspect ofthe invention.

7 EXAMPLE B (Per 10 ml. dose) Lactic acid (USP. 85%) mg 500 Aluminumchlorhydroxide complex mg 225 Aluminum chloride, hydrous (U.S.P.) mg 350Quinoline yellow, water soluble D. and C. Yellow No. mg 1.5 TartrazineF. D. and C. Yellow No. 5 mg. 0.25 Aromatics mg 60.0 10 Octylphenoxypolyethoxy ethanol Triton X100 mg 150.0 Ethyl alcohol (USP. 95%) ml 3.15Water, q.s. ml 10.0

Aromatics: Gm. Menthol 29.6 Thymol 29.6 Oil eucalyptus 38.6 Methylsalicylate 2.2

To make the douche preparation the water is separated into two moieties.In one portion the lactic acid, aluminum chlorhydroxide complex,aluminum chloride, quinoline and tartrazine are dissolved in the amountsshown above for each 5 ml. quantity in the moiety. In the other moietythe alcohol, aromatics and surfactant are dissolved in the quantitiesshown per 5 ml. of moiety.

Clinical data Clinical evaluation of the composition of Example B wascompleted with 59 subjects. The patients used the medication 3 to 7times weekly for 24 doses. It was used as a cleansing douche and asadjunct for other vaginal therapy. The patients were instructed to add10 ml. (a measuring device was provided) to 1 quart of water, and thendouche.

Results: Irritation, burning, undesirable side eifects, none; prefer todouche powders, 57.

The product was described by the patients as soothing, refreshing,excellent, easy to prepare, and convenient. In addition, as is known tothose skilled in the art, aluminum salts confer the desired astringencyon the compositions. The unique combination of water-soluble astringentsemployed herein were found particularly effective in the clinicalevaluation.

The example which follows illustrates the invention when isopropylalcohol is used, the method of preparation being the same as in ExampleB.

Combinations of an aluminum chlorhydroxide complex and aluminum chloridehave not, to our knowledge, been employed as astringents for the vaginaltract. In addition it was not realized that their use in combinationwith lactic acid would provide a composition possessing the buffercapacity of the douche preparation of this invention. When used in aweight ratio in the range of 1 aluminum chlorhydroxide complex:1.5aluminum chloride:2 lactic acid, to 1 aluminum chlorhydroxide complex:2aluminum chloride:3 lactic acid resulting in a pH of 3.5 to 5, a doucheproduct with good buffer capacity results. Using the foregoing ratiosthe ingredients are employed in ranges set forth hereinbefore. Thealuminum chlorhydroxide complex and aluminum chloride are the bufferingredients, constituting 1.5 to 20 pehcent of the composition.

Thus this invention provides not only a liquid douche preparationcontaining aromatics, but a liquid douche preparation containing new andunique astringents. All of the advantages of lactic acid douches areattained by the preparations of the invention. Obviously changes in theother ingredients can be made. For example several combinations ofaromatics can be employed, and these can be varied depending on thealcohol employed. These and other obvious ramifications and variationsare, of course, within the scope of this invention.

What is claimed is:

1. A concentrated liquid douche preparation containing aromatics, saidpreparation being water dilutable to form an aqueous douche forrestoring and maintaining a normal vaginal pH, said preparation being abuffered aqueous solution of lactic acid having a pH of 3.5 to 5 andcontaining a Wetting agent selected from the group consisting ofnonionic surfactants and sodium lauryl sulfate, and, dissolved therein,an alcohol solution of aromatics selected from the group consisting ofmenthol, thymol, oil of eucalyptus, methyl salicylate and mixturesthereof, the alcohol permitting solution of the aromatics in thebuffered aqueous acid solution, the alcohol being selected from thegroup consisting of ethyl and isopropyl alcohols, essentially noreaction of these alcohols with lactic acid occurring to raise the pH,the solution containing 96 to 74 Weight percent lactic acid, 2 to 14percent wetting agent, 2 to 12 Weight percent aromatics, the total beingpercent, and at least suflicient alcohol to dissolve the aromatics.

2. A concentrated liquid douche preparation containing aromatics, saidpreparation being water dilutahle to form an aqueous douche forrestoring and maintaining a normal vaginal pH, said preparation being abuttered aqueous solution of lactic acid having a pH of 3.5 to 5 andcontaining a nonionic surfactant, and, dissolved therein, an ethanolsolution of aromatics selected from the group consisting of menthol,thymol, oil of eucalyptus, methyl salicylate and mixtures thereof, theethanol permitting solution of the aromatics in the buffered aqueousacid solution, essentially no reaction of ethanol with lactic acidoccurring to raise the pH, the solution containing 96 to 75 weightpercent lactic acid, 2 to 14 percent surfactant, 2 to 12 weight percentaromatics, the total being 100 percent, and at least suflicient ethanolto dissolve the aromatics.

3. The douche preparation of claim 2 wherein the surfactant is anoctylphenoxy polyether ethanol having three to thirty oxyethylenegroups.

4. A concentrated douche preparation, said preparation being waterdilutable to form an aqueous douche for restoring and maintaining anormal vaginal pH, said preparation containing in aqueous solution 96 to74 weight percent lactic acid as an active ingredient,

2 to 14 weight percent of a nonionic surfactant,

2 to 12 weight percent aromatics selected from the group consisting ofmenthol, thymol, oil of eucalyptus, methyl salicylate and mixturesthereof,

the total being 100 percent,

aluminum chlorhydroxide and aluminum chloride as astringents and bufferingredients to maintain a pH of 3.5 to 5,

the Weight ratio of aluminum chlorhydroxide to aluminum chloride tolactic acid being in the range of 1:1.5:2 to 1:2:3, and

ethanol,

the ethanol having the aromatics dissolved therein permitting solutionof the aromatics in the aqueous lactic acid solution with essentially noreaction with lactic acid raising the pH, the volume of ethanol beingfrom sufficient to dissolve the aromatics to 50 percent of the aqueoussolution in volume.

5. A concentrated douche preparation, said preparation being Waterdilutable to form an aqueous douche for restoring and maintaining anormal vaginal pH, said preparation containing in aqueous solution 96 to74 Weight percent lactic acid as an active ingredient,

2 to 14 Weight percent of a nonionic surfactant,

2 to 12 Weight percent aromatics selected from the group consisting ofmenthol, thymol, oil of eucalyptus, methyl salicylate and mixturesthereof,

the total being 100 percent,

aluminum chlorhydroxide and aluminum chloride as astringents and bufferingredients to maintain a pH of 3.5 to 5,

the Weight ratio of aluminum chlorhydroxide to aluminum chloride tolactic acid being in the range of 1:1.5:2 to 1:2:3, and

isopropanol,

the isopropanol having the aromatics dissolved therein permittingsolution of the aromatics in the aqueous lactic acid solution withessentially no reaction With lactic acid raising the pH, the volume ofisopropanol being from sufiicient to dissolve the aromatics to 50percent of the aqueous solution in volume.

References Cited UNITED STATES PATENTS 2,556,567 6/1951 Wright et al.167-58 2,649,398 8/1953 Wright et al 167-58 2,904,468 9/1959 Davis etal. 167-58 3,026,247 3/ 1962 Hill 167-22 FOREIGN PATENTS 1,306,6489/1962 France.

ALBERT T, MEYERS, Primary Examiner. I. S. LEVITT, Examiner V. C. CLARKE,Assistant Examiner

1. A CONCENTRATED LIQUID DOUCHE PREPARTION CONTAINING AROMATICS, SAIDPREPARATION BEING WATER DILUTABLE TO FORM AN AQUEOUS DOUCHE FORRESTORING AND MAINTAINING A NORMAL VAGINAL PH, SAID PREPARATION BEING ABUFFERED AQUEOUS SOLUTION OF LACTIC ACID HAVING A PH OF 3.5 TO 5 ANDCONTAINING A WETTING AGENT SELECTED FROM THE GROUP CONSISTING OFNONIONIC SURFACTANTS AND SODIUM LAURYL SULFATE, AND, DISSOLVED THEREIN,AN ALCOHOL SOLUTION OF AROMATICS SELECTED FROM THE GROUP CONSISTING OFMENTHOL, THYMOL, OIL OF EUCALYPTUS, METHYL SALICYLATE AND MIXTURESTHEREOF, THE ALCOHOL PERMITTING SOLUTION OF THE AROMATICS IN THEBUFFERED AQUEOUS ACID SOLUTION, THE ALCOHOL BEING SELECTED FROM THEGROUP CONSISTING OF ETHYL AND ISOPROPYL ALCOHOLS, ESSENTIALLY NOREACTION OF THESE ALCOHOLS WITH LACTIC ACID OCCURRING TO RAISE THE PH,THE SOLUTION CONTAINING 96 TO 74 WEIGHT PERCENT LACTIC ACID, 2 TO 14PERCENT WETTING AGENT, 2 TO 12 WEIGHT PERCENT AROMATICS, THE TOTAL BEING100 PERCENT, AND AT LEAST SUFFICIENT ALCOHOL TO DISSOLVE THE AROMATICS.